Immunogenic cell death as a mechanism of synergy between sunitinib and 177Lu-DOTATATE peptide receptor radionuclide therapy in pancreatic neuroendocrine tumors

Peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-DOTATATE improves outcomes in neuroendocrine tumors (NETs), yet durable disease control remains limited in progressive pancreatic NET (pNET) and higher-grade disease. Combinations that enhance PRRT efficacy may be advantageous. As sunitinib has radiosensitizing and immunomodulatory effects, we explored the clinical activity and mechanistic basis of combining sunitinib with PRRT. Combination treatment with ¹⁷⁷Lu-DOTATATE (1-3 cycles; 7.4 GBq per cycle) and sunitinib at 37.5 mg/day was well tolerated and effective in a pilot group of heavily pretreated pNET patients with progressive disease. Treatment response was assessed by ⁶⁸Ga-DOTATOC PET/CT and serum tumor markers (CgA, NSE). Mechanistic studies were performed in QGP-1 pNET cells using proliferation and apoptosis assays, cell-cycle analysis, and immunogenic cell death (ICD) markers. Combination therapy was well tolerated and induced marked responses: three patients achieved near-complete responses and two partial responses on post-therapy ⁶⁸Ga-DOTATOC PET/CT. In vitro, ¹⁷⁷Lu-DOTATATE and sunitinib showed bidirectional sensitization: low-dose sunitinib reduced the LD50 of ¹⁷⁷Lu-DOTATATE, and low-activity ¹⁷⁷Lu-DOTATATE reduced the LD50 of sunitinib. ¹⁷⁷Lu-DOTATATE induced dose-dependent PARP cleavage and S/G2-M arrest; however, sunitinib shifted cell death toward late apoptosis/necrosis. The combination produced a more-than-additive increase in calreticulin exposure on the tumor cell surface and enhanced HMGB1 but not interleukin- 1ß- or interleukin-18-release compared with either monotherapy, indicating immunogenic late apoptosis/necrosis, without canonical inflammasome activation. Intermittent sunitinib combined with ¹⁷⁷Lu-DOTATATE PRRT demonstrated encouraging activity in progressive pNET. The mechanism of synergy in vitro was enhanced ICD, suggesting that immune responses contribute to the synergy in vivo.